Atrial Fibrillation in Hyperthyroidism: Active Antibodies to Autonomic Receptors

甲状腺功能亢进症中的心房颤动：自主神经受体的活性抗体

• 批准号: 8391090
• 负责人: David Kem
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391090
• 关键词: Action Potentials; Acute; Address; Adrenergic Agents; Adrenergic Agonists; Age; Aging; Animal Model; Animals; Antibodies; Anticoagulants; Atrial Fibrillation; Autoantibodies; Autoimmune Process; Biological Assay; Canis familiaris; Cardiac; Cells; Chronic; Cyclic AMP; Data; Databases; Development; Electrocardiogram; Epidemiologic Studies; Experimental Models; Fluorescence; Fluorescence Resonance Energy Transfer; Functional disorder; Future; Ganglia; General Population; Healthcare; Heart; Heart Atrium; Heart Diseases; Heart Rate; Heart failure; Human; Hyperactive behavior; Hyperthyroidism; Immune; In Vitro; Lead; Ligands; Maps; Measures; Mediating; Modeling; Morbidity - disease rate; Muscarinic Antagonists; Muscarinic M2 Receptor; Optics; Oryctolagus cuniculus; Patients; Perfusion; Population; Prevalence; Property; Pulmonary veins; Risk Factors; Role; Serum; Signal Transduction; Sinus; Source; Stroke; Stroke prevention; Tachyarrhythmias; Telemetry; Therapeutic; Thyroid Hormones; Veterans; adrenergic; age related; base; fluorescence imaging; in vivo; insight; medical attention; mortality; normal aging; older patient; public health relevance; receptor; tissue preparation

DESCRIPTION (provided by applicant): The large majority of older patients with autoimmune Graves' hyperthyroidism and atrial fibrillation (AF) have coexisting activating autoantibodies (AA) to the beta1-adrenergic (B1AR) and M2 muscarinic receptors (M2R). Adrenergic and muscarinic agonists are known to enhance the likelihood for developing AF. HYPOTHESIS: AA in the aging thyrotoxic heart facilitates and/or causes AF. We have demonstrated AABAR) in 94% and AAM2R in 88%; and both autoantibodies in 83% in Graves' hyperthyroidism + AF compared to 10% of Graves' patients in normal sinus rhythm (P<0.001). All patients with AF had at least one of the two AA. These autoantibodies altered electrophysiological activity in pulmonary vein atrial sleeve cells such as predisposes to AF in experimental models; supporting our concept that elevated AABAR and AAM2R as well as thyroid hormone are major risk factors for AF. PROPOSAL: We will use translational and mechanistic studies to examine the electrophysiological interrelationships of thyroid hormone, age and activating autoantibodies as a cause of AF. METHODS: (Spec. Aim A) Expansion of epidemiological studies to identify the prevalence and function of autoantibodies in non-Graves" hyperthyroidism and AF; (Spec. Aim Bi) Identify age and thyroid hormone dependent triggering of ectopic action potentials in the presence of target-specific autonomic AA in a canine pulmonary vein atrial sleeve tissue preparation in vitro; (Spec. Aim Bii) Study the development of AF (by ECG telemetry) in young (6 mo) and old (>5yrs) rabbits immunized to produce target-specific AAB1AR and/or AAM2R without and with thyroid hormone. We will then use sophisticated electrophysiological studies incorporating right atrial ganglia stimulation to measure the pulmonary vein atrial sleeve cell threshold for induction of AF. This model will determine the combined effects of AABAR and AAM2R on the atrial substrate for AF. METHODS also include a FRET-based micro-cAMP assay to examine the allosteric effects of AA. This assay will assist in determining whether these AA act as agonists and whether they also serve as partial antagonists to their normally operative orthosteric ligands. Our studies are NOVEL in that they will identify a spectrum of activating autoantibodies in the heart and demonstrate their role in immune-mediated mechanism(s) leading to AF in hyperthyroidism. Our data are relevant not only to hyperthyroidism but will also lead to a better understanding of these mechanisms in other and more common forms of AF which frequently coexist with AA. POTENTIAL IMPACT ON VETERANS HEALTH CARE: AF is an important risk factor for stroke and heart failure in our aging veteran population and leads to increased mortality and morbidity. The present study addresses this issue and may permit identification of future therapeutic options.

描述（由申请人提供）： 大多数患有自身免疫性格雷夫斯甲状腺功能亢进症和心房颤动 (AF) 的老年患者同时存在针对 β1 肾上腺素能 (B1AR) 和 M2 毒蕈碱受体 (M2R) 的激活自身抗体 (AA)。已知肾上腺素能和毒蕈碱激动剂会增加发生房颤的可能性。假设：老化的甲状腺毒性心脏中的 AA 会促进和/或导致 AF。我们证明了 AABAR) 的准确率达到 94%，AAM2R 的准确率达到 88%；格雷夫斯甲状腺功能亢进 + 房颤患者中两种自身抗体的比例为 83%，而正常窦性心律的格雷夫斯患者中这一比例为 10%（P<0.001）。所有 AF 患者至少有两种 AA 中的一种。这些自身抗体改变了肺静脉心房袖细胞的电生理活动，例如在实验模型中容易发生房颤；支持我们的观点，即 AABAR 和 AAM2R 以及甲状腺激素升高是 AF 的主要危险因素。建议：我们将利用转化和机制研究来检查甲状腺激素、年龄和激活自身抗体作为 AF 病因的电生理相互关系。方法：（规范目标 A）扩大流行病学研究，以确定非 Graves 甲状腺功能亢进症和房颤中自身抗体的患病率和功能；（规范目标 Bi）确定存在以下情况时异位动作电位的年龄和甲状腺激素依赖性触发：犬肺静脉心房袖组织制备中的目标特异性自主 AA（Spec. Aim Bii）研究年轻人 AF 的发展（通过心电图遥测）； （6 个月）和老年（> 5 岁）兔子经过免疫产生靶标特异性 AAB1AR 和/或 AAM2R，不使用或使用甲状腺激素，然后我们将使用复杂的电生理学研究结合右心房神经节刺激来测量肺静脉心房袖细胞阈值。该模型将确定 AABAR 和 AAM2R 对 AF 心房基质的综合影响。方法还包括基于 FRET 的 micro-cAMP 测定法来检查 AF。该测定将有助于确定这些 AA 是否充当激动剂以及它们是否也充当其正常作用的正位配体的部分拮抗剂。我们的研究是新颖的，因为它们将识别心脏中一系列激活的自身抗体，并证明它们在导致甲状腺功能亢进房颤的免疫介导机制中的作用。我们的数据不仅与甲状腺功能亢进相关，而且还将有助于更好地理解其他更常见的 AF 形式（经常与 AA 共存）的这些机制。对退伍军人医疗保健的潜在影响：房颤是老年退伍军人中中风和心力衰竭的重要危险因素，并导致死亡率和发病率增加。本研究解决了这个问题，并可能有助于确定未来的治疗选择。